The present invention is generally related to novel heteroaromatic substituted amide compounds and more particularly to heteroaromatic substituted amide compounds showing antagonist activity To neurokinin 1 (NK-1, substance P) receptors.
The neuropeptide receptor for substance P (NK-1) is widely distributed throughout the mammalian nervous system (especially brain and spinal ganglia), the circulatory system and peripheral tissues (especially the duodenum and jejunum) and are involved in regulating a number of diverse biological processes. The central and peripheral actions of the mammalian tachykinin substance P have been associated with numerous inflammatory conditions including migraine, rheumatoid arthritis, asthma, and inflammatory bowel disease as well as mediation of the emetic reflex and the modulation of central nervous system (CNS) disorders such as Parkinson""s disease (Neurosci. Res ., 1996, 7, 187-214), anxiety (Can. J. Phys., 1997, 75, 612-621) and depression (Science, 1998, 281, 1640-1645).
xe2x80x9cTachykinin Receptor and Tachykinin Receptor Antagonistsxe2x80x9d, J. Auton. Pharmacol., 13, 23-93, 1993 reviews evidence for the usefulness of tachykinin receptor antagonists in pain, headache, especially migraine, Alzheimer""s disease, multiple sclerosis, attenuation of morphine withdrawal, cardiovascular changes, oedema, such as oedema caused by thermal injury, chronic inflammatory diseases such as rheumatoid arthritis, asthma/bronchial hyperreactivity and other respiratory diseases including allergic rhinitis, inflammatory diseases of the gut including ulcerative colitis and Crohn""s disease, ocular injury and ocular inflammatory diseases. The neurokinin-1 receptor antagonists are also known to be useful for the treatment of motion sickness and for treatment of induced vomiting.
Furthermore, Neurokinin 1 receptor antagonists are being developed for the treatment of a number of physiological disorders associated with an excess or imbalance of tachykinin, in particular substance P. Examples of conditions in which substance P has been implicated include disorders of the central nervous system such as anxiety, depression and psychosis (WO 95/16679, WO 95/18124 and WO 95/23798).
In addition, a paper published in The New England Journal of Medicine, Vol. 340, No. 3 190-195, 1999 describes the reduction of cisplatin-induced emesis by a selective neurokinin-1-receptor antagonist.
U.S. Pat. No. 5,972,938 discloses a method for treating a psychoimmunologic or a psychosomatic disorder by administration of a tachykinin receptor, such as NK-1 receptor antagonist.
The usefulness of neurokinin 1 receptor antagonists for the treatment of certain forms of urinary incontinence is further described in xe2x80x9cNeuropeptides, 32(1), 1-49, (1998)xe2x80x9d and xe2x80x9cEur. J. Pharmacol., 383(3), 297-303, (1999)xe2x80x9d.
NK1 receptor antagonists also have been reported to have a beneficial effect in the therapy of traumatic brain injury in a paper presented by Professor Nimmo at the International Tachykinin Conference 2000 in La Grande Motte, France, Oct. 17-20, 2000 with the title xe2x80x9cNeurokinin 1 (NK-1) Receptor Antagonists Improve the Neurological Outcome Following Traumatic Brain Injuryxe2x80x9d (Authors: A. J. Nimmo, C. J. Bennett, X. Hu, I. Cernak, R. Vink).xe2x80x9d
The present invention relates to compounds having the formulae 
wherein
R1 is 
xe2x80x94NH(CH2)2OH or xe2x80x94NR3C(O)R4;
R2 is methyl or chloro;
R3 is hydrogen or methyl;
R4 is lower alkyl or lower cycloalkyl;
R is hydrogen or xe2x80x94(CH2)2OH; and
n is 1 or 2
or a pharmaceutically acceptable acid addition salt thereof.
A 4-phenyl-pyridine compound, related to compounds disclosed in the present application, is disclosed in U.S. App. Ser. No. 09/507,456.
The compounds of formulae IA and IB can also be used in form of their prodrugs. Examples are esters, N-oxides, phosphate esters, glycoamide esters, glyceride conjugates and the like. The prodrugs may add to the value of the present compound""s advantages in adsorption, pharmacokinetics in distribution and transport to the brain.
The compounds of formulae IA and IB and their salts are characterized by valuable therapeutic properties. It has been surprisingly found that the compounds of the present invention are antagonists of the Neurokinin 1 (NK-1, substance P) receptor. Substance P is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, the latter being so-named because of their prompt contractile action on extravascular smooth muscle tissue. The receptor for substance P is a member of the superfamily of G protein-coupled receptors therefore, the compounds of the invention can be used to treat diseases associated with an excess or imbalance of tachykinin, in particular substance P. Examples of conditions in which substance P has been implicated include disorders of the central nervous system such as anxiety, depression and psychosis.
The following definitions of the general terms used in the present description apply irrespective of whether the terms in question appear alone or in combination. As used herein, the term xe2x80x9clower alkylxe2x80x9d denotes a straight- or branched-chain alkyl group containing from 1-7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, t-butyl and the like. Preferred lower alkyl groups are groups with 1-4 carbon atoms. Particularly preferred are methyl groups. The term xe2x80x9ccycloalkylxe2x80x9d denotes a saturated carbocyclic group, containing 3-6 carbon atoms. A preferred cycloalkyl group is cyclopropyl.
Exemplary preferred are compounds of formula IA, in which R2 is methyl, for example the following compounds:
N-(3,5-bis-trifluoromethyl-benzyl)-N-methyl-4-o-tolyl-6-[1,2,4]triazol-1-yl-nicotinamide,
N-(3,5-bis-trifluoromethyl-benzyl)-6-(2-hydroxy-ethylamino)-N-methyl-4-o-tolyl-nicotinamide,
4-hydroxy-4xe2x80x2-o-tolyl-3,4,5,6-tetrahydro-2H-[1,2xe2x80x2]bipyridinyl-5xe2x80x2-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
4-(2-hydroxy-ethoxy)-4xe2x80x2-o-tolyl-3,4,5,6-tetrahydro-2H-[1,2xe2x80x2]bipyridinyl-5xe2x80x2-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide or
(R)-N-(3,5-bis-trifluoromethyl-benzyl)-6-(3-hydroxy-pyrrolidin-1-yl)-N-methyl-4-o-tolyl-nicotinamide.
Further preferred are compounds of formula IA, in which R2 is chloro.
An example of such compound is:
4xe2x80x2-(2-chloro-phenyl)-4-hydroxy-3,4,5,6-tetrahydro-2H-[1,2xe2x80x2]bipyridinyl-5xe2x80x2-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide
Exemplary preferred are compounds of formula IB, in which R2 is methyl, for example the following compounds:
2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(2-hydroxy-ethylamino)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,
2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(2,3-dihydro-[1,4]oxazin-4-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,
N-(6-acetylamino-4-o-tolyl-pyridin-3-yl)-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,
N-[6-(acetyl-methyl-amino)-4-o-tolyl-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,
cyclopropanecarboxylic acid (5-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino }-4-o-tolyl-pyridin-2-yl)-amide,
cyclopropanecarboxylic acid (5-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4-o-tolyl-pyridin-2-yl)-methyl-amide or
2-(3,5-bis-trifluoromethyl-phenyl)-N-(6-imidazol-1-yl-4-o-tolyl-pyridin-3-yl)-N-methyl-isobutyramide.
Further preferred are compounds of formula IB, in which R2 is chloro, for example the following compound:
2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide.
Also preferred are compounds of formula 1B, in which R1 is xe2x80x94NH(CH)2OH. Also for formula 1B, R1 is preferred as xe2x80x94N R3C(O) R4, R3 is methyl and R4 is lower alkyl. R4 being methyl is particularly preferred. Additionally, R4 is preferred as cycloalkyl, particularly cyclopropyl. Additionally, for formula 1B, R1 is preferred as a heterocycle, with oxazine and imidazole being preferred heterocycles when R2 is methyl.
The present compounds of formulae IA and IB and their pharmaceutically acceptable salts can be prepared by methods known in the art, for example, by processes described below, which process comprises reacting a compound of formula 
with a compound of formula 
to a compound of formula 
wherein R1 and R2 have the significances given above, or reacting a compound of formula 
with a compound of formula 
to give a compound of formula 
wherein R1 and R2 have the significances given above, or reacting a compound of formula 
with a compound of formula 
to a compound of formula 
wherein Z is Cl, Br, I, xe2x80x94OS(O)2C6H4CH3 or xe2x80x94OS(O)2CH3 and the other definitions of substituents are given above, or reacting a compound of formula 
with a compound of formula
R1Hxe2x80x83xe2x80x83XIV
to a compound of formulae 
wherein the definition of substituents is given above, and if desired, converting the compound obtained into a pharmaceutically acceptable acid addition salt.
In accordance with process variant a) DIPEA (N-ethyldiisopropyl-amine) is added to a mixture of a compound of formula II and a compound of formula III in dichloromethane and the mixture is stirred at temperatures between 35-40xc2x0 C. The desired compound of formula IB is isolated after purification in good yields.
Process variant b) describes the reaction of a compound of formula IV with a compound of formula V to a compound of formula IA. The reaction is carried out in conventional manner, for example in a solvent, such as a mixture of toluene and triethylamine. The mixture is refluxed for about 1 hour.
Process variant c) describes the reaction of a compound of formula VI with a compound of formula VII to a compound of formula IA. This reaction is carried out by deprotonation of a compound of formula VI with KHMDS (potassium hexamethyldisilazide) and subsequent addition of a compound of formula VII. A suitable solvent is tetrahydrofuran. The reaction is carried out at room temperature.
A further method for the preparation of a compound of formula IA or IB is described in process variant d). A compound of formulae VIII or IX is treated with a compound of formula XIV, which is, for example, 1,2,4-triazole, ethanolamine, 4-hydroxypiperidine, (R)-3-pyrrolidinol or morpholine. The reaction is carried out in THF, usually at 80-140xc2x0 C.
The salt formation is effected at room temperature in accordance with methods which are known per se and which are familiar to any person skilled in the art. Not only salts with inorganic acids, but also salts with organic acids come into consideration. Hydrochlorides, hydrobromides, sulphates, nitrates, citrates, acetates, maleates, succinates, methan-sulphonates, p-toluenesulphonates and the like are examples of such salts.
The following schemes 1-3 describe the processes for preparation of compounds of formulae IA and IB in more detail. The starting materials are known compounds or may be prepared according to methods known in the art.
In the schemes the following abbreviations have been used:
PivCl pivaloyl chloride
THF tetrahydrofuran
TMEDA N,N,Nxe2x80x2,Nxe2x80x2-tetramethylethylene diamine
DIPEA N-ethyldiisopropyl-amine
KHMDS potassium hexamethyldisilazide 
The definition of substituents is described above. 
The definition of substituents is described above 
The definition of substituents is described above.
The most preferred indications in accordance with the present invention are those, which include disorders of the central nervous system, for example the treatment or prevention of certain depressive disorders or emesis by the administration of NK-1 receptor antagonists. A major depressive episode has been defined as being a period of at least two weeks during which, for most of the day and nearly every day, there is either depressed mood or the loss of interest or pleasure in all, or nearly all activities.
As mentioned earlier, the compounds of formulae IA and IB and their pharmaceutically usable addition salts possess valuable pharmacological properties. It has been found that the compounds of the present invention are antagonists of the Neurokinin 1 (NK-1 substance P) receptor.
The compounds were investigated in accordance with the tests given hereinafter.
The affinity of test compounds for the NK1 receptor was evaluated at human NK1 receptors in CHO cells infected with the human NK1 receptor (using the Semliki virus expression system) and radiolabelled with [3H]substance P (final concentration 0.6 nM). Binding assays were performed in HEPES buffer (50 mM, pH 7.4) containing BSA (0.04%) leupeptin (8 xcexcg/ml), MnCI2 (3 mM) and phosphoramidon (2 xcexcM). Binding assays consisted of 250 xcexcl of membrane suspension (1.25xc3x97105 cells/assay tube), 0.125 xcexcl of buffer of displacing agent and 125 xcexcl of [3H]substance P. Displacement curves were determined with at least seven concentrations of the compound. The assay tubes were incubated for 60 min at room temperature after which time the tube contents were rapidly filtered under vacuum through GF/C filters presoaked for 60 min with PEI (0.3%) with 2xc3x972 ml washes of HEPES buffer (50 mM, pH 7.4). The radioactivity retained on the filters was measured by scintillation counting. All assays were performed in triplicate in at least 2 separate experiments.
The affinity to the NK-1 receptor, given as pKi, is in the scope of 8.40-9.24 for the described exemplary compounds of the present invention.
The compounds the present invention of formulae IA and IB as well as their pharmaceutically usable acid addition salts can be used as medicaments, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragxc3xa9es, hard and soft gelatine capsules, solutions, emulsions or suspensions. The administration can, however, also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.
The compounds of formulae IA and IB and their pharmaceutically usable acid addition salts can be processed with pharmaceutically inert, inorganic or organic excipients for the production of tablets, coated tablets, dragees and hard gelatine capsules. Lactose, cornstarch or derivatives thereof, talc, stearic acid or its salts etc. can be used as such excipients e.g. for tablets, dragxc3xa9es and hard gelatine capsules.
Suitable excipients for soft gelatine capsules are e.g. vegetable oils, waxes, fats, semi-solid and liquid polyols etc.
Suitable excipients for the manufacture of solutions and syrups are e.g. water, polyols, saccharose, invert sugar, glucose etc.
Suitable excipients for injection solutions are e.g. water, alcohols, polyols, glycerol, vegetable oils etc.
Suitable excipients for suppositories are. e.g. natural or hardened oils, waxes, fats, semi-liquid or liquid polyols etc.
Moreover, the pharmaceutical preparations can contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
The dosage can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, the effective dosage for oral or parenteral administration is between 0.01-20 mg/kg/day, with a dosage of 0.1-10 mg/kg/day being preferred for all of the indications described. The daily dosage for an adult human being weighing 70 kg accordingly lies between 0.71-1400 mg per day, preferably between 7 and 700 mg per day.
The following Examples illustrate the present invention without limiting it. All temperatures are given in degrees Celsius.